Ticagrelor

WARNING: BLEEDING RISK Ticagrelor, like other antiplatelet agents, can cause significant, sometimes fatal bleeding ( 5.1 , 6.1 ). Do not use ticagrelor in patients with active pathological bleeding or a history of intracranial hemorrhage ( 4.1 , 4.2 ). Do not start ticagrelor in patients undergoing urgent coronary artery bypass graft surgery (CABG) ( 5.1 , 6.1 ). If possible, manage bleeding without discontinuing ticagrelor. Stopping ticagrelor increases the risk of subsequent cardiovascular events ( 5.2 ). See full prescribing information for complete boxed warning. Ticagrelor, like other antiplatelet agents, can cause significant, sometimes fatal bleeding. ( 5.1 , 6.1 ) Do not use ticagrelor in patients with active pathological bleeding or a history of intracranial hemorrhage. ( 4.1 , 4.2 ) Do not start ticagrelor in patients undergoing urgent coronary artery bypass graft surgery (CABG). ( 5.1 , 6.1 ) If possible, manage bleeding without discontinuing ticagrelor. Stopping ticagrelor increases the risk of subsequent cardiovascular events. ( 5.2 )

5 WARNINGS AND PRECAUTIONS Dyspnea was reported more frequently with ticagrelor than with control agents in clinical trials. Dyspnea from ticagrelor is self-limiting. ( 5.3 ) Severe Hepatic Impairment: Likely increase in exposure to ticagrelor. ( 5.5 ) Laboratory Test Interference: False negative platelet functional test results have been reported for Heparin Induced Thrombocytopenia (HIT). Ticagrelor is not expected to impact PF4 antibody testing for HIT ( 5.7 ). 5.1 Risk of Bleeding Drugs that inhibit platelet function including ticagrelor increase the risk of bleeding [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] . Patients treated for acute ischemic stroke or TIA Patients at NIHSS >5 and patients receiving thrombolysis were excluded from THALES and use of ticagrelor in such patients is not recommended. 5.2 Discontinuation of Ticagrelor in Patients Treated for Coronary Artery Disease Discontinuation of ticagrelor will increase the risk of myocardial infarction, stroke, and death in patients being treated for coronary artery disease. If ticagrelor must be temporarily discontinued (e.g., to treat bleeding or for significant surgery), restart it as soon as possible. When possible, interrupt therapy with ticagrelor for five days prior to surgery that has a major risk of bleeding. Resume ticagrelor as soon as hemostasis is achieved. 5.3 Dyspnea In clinical trials, about 21% (THEMIS) of patients treated with ticagrelor developed dyspnea. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment but led to study drug discontinuation in 1.0% (THALES) and 6.9% (THEMIS) of patients. If a patient develops new, prolonged, or worsened dyspnea that is determined to be related to ticagrelor, no specific treatment is required; continue ticagrelor without interruption if possible. In the case of intolerable dyspnea requiring discontinuation of ticagrelor, consider prescribing another antiplatelet agent. 5.4 Bradyarrhythmias Ticagrelor can cause ventricular pauses [see Adverse Reactions ( 6.1 )] . Bradyarrhythmias including AV block have been reported in the postmarketing setting. Patients with a history of sick sinus syndrome, 2 nd or 3 rd degree AV block or bradycardia-related syncope not protected by a pacemaker were excluded from clinical studies and may be at increased risk of developing bradyarrhythmias with ticagrelor. 5.5 Severe Hepatic Impairment Avoid use of ticagrelor in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor. There are no studies of ticagrelor patients with severe hepatic impairment [see Clinical Pharmacology ( 12.3 )] . 5.6 Central Sleep Apnea Central sleep apnea (CSA) including Cheyne-Stokes respiration (CSR) has been reported in the post-marketing setting in patients taking ticagrelor, including recurrence or worsening of CSA/CSR following rechallenge. If central sleep apnea is suspected, consider further clinical assessment. 5.7 Laboratory Test Interferences False negative functional tests for Heparin Induced Thrombocytopenia (HIT) Ticagrelor has been reported to cause false negative results in platelet functional tests (including the heparin-induced platelet aggregation (HIPA) assay) for patients with Heparin Induced Thrombocytopenia (HIT). This is related to inhibition of the P2Y 12 -receptor on the healthy donor platelets in the test by ticagrelor in the affected patient’s serum/plasma. Information on concomitant treatment with ticagrelor is required for interpretation of HIT functional tests. Based on the mechanism of ticagrelor interference, ticagrelor is not expected to impact PF4 antibody testing for HIT.

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: Bleeding [see Warnings and Precautions ( 5.1 )] Dyspnea [see Warnings and Precautions ( 5.3 )] Most common adverse reactions (>5%) are bleeding and dyspnea. ( 5.1 , 5.3 , 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hisun Pharmaceuticals USA, Inc. at 1-855-554-4786 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Ticagrelor has been evaluated for safety in more than 58,000 patients. Bleeding in THEMIS (Prevention of major CV events in patients with CAD and Type 2 Diabetes Mellitus) The Kaplan-Meier curve of time to first TIMI Major bleeding event is presented in Figure 3. Figure 3 - Time to first TIMI Major bleeding event (THEMIS) T = Ticagrelor; P = Placebo; N = Number of patients The bleeding events in THEMIS are shown below in Table 6. Table 6 – Bleeding events (THEMIS) Ticagrelor N=9562 Placebo N=9531 Events / 1000 patient years Events / 1000 patient years TIMI Major 9 4 TIMI Major or Minor 12 5 TIMI Major or Minor or Requiring medical attention 46 18 Fatal bleeding 1 0 Intracranial hemorrhage 3 2 Bleeding in THALES (Reduction in risk of stroke in patients with acute ischemic stroke or TIA) The Kaplan-Meier curve of time course of GUSTO severe bleeding events is presented in Figure 4. Figure 4 - Time course of GUSTO severe bleeding events KM%: Kaplan-Meier percentage evaluated at Day 30; T = Ticagrelor; P = placebo; N = Number of patients GUSTO Severe : Any one of the following: fatal bleeding, intracranial bleeding (excluding asymptomatic hemorrhagic transformations of ischemic brain infarctions and excluding microhemorrhages < 10 mm evident only on gradient-echo magnetic resonance imaging), bleeding that caused hemodynamic compromise requiring intervention (eg, systolic blood pressure <90 mmg Hg that required blood or fluid replacement, or vasopressor/inotropic support, or surgical intervention). Intracranial bleeding and fatal bleeding in THALES: In total, there were 21 intracranial hemorrhages (ICHs) for ticagrelor and 6 ICHs for placebo. Fatal bleedings, almost all ICH, occurred in 11 for ticagrelor and in 2 for placebo. Bradycardia THEMIS and THALES excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2 nd or 3 rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker). 15 16 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ticagrelor. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Thrombotic Thrombocytopenic Purpura (TTP) has been rarely reported with the use of ticagrelor. TTP is a serious condition which can occur after a brief exposure (<2 weeks) and requires prompt treatment. Immune system disorders: Hypersensitivity reactions including angioedema [see Contraindications ( 4.3 )]. Respiratory Disorders: Central sleep apnea, Cheyne-Stokes respiration Skin and subcutaneous tissue disorders: Rash

<table border="1" cellpadding="0" cellspacing="0" width="100.0%"><tbody><tr><td rowspan="2"><paragraph/></td><td><paragraph><content styleCode="bold">Ticagrelor</content></paragraph><paragraph><content styleCode="bold">N=9562</content></paragraph></td><td><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N=9531</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Events / 1000 patient years</content></paragraph></td><td><paragraph><content styleCode="bold">Events / 1000 patient years</content></paragraph></td></tr><tr><td><paragraph>TIMI Major</paragraph></td><td><paragraph>9</paragraph></td><td><paragraph>4</paragraph></td></tr><tr><td><paragraph>TIMI Major or Minor</paragraph></td><td><paragraph>12</paragraph></td><td><paragraph>5</paragraph></td></tr><tr><td><paragraph>TIMI Major or Minor or Requiring medical attention</paragraph></td><td><paragraph>46</paragraph></td><td><paragraph>18</paragraph></td></tr><tr><td><paragraph>Fatal bleeding</paragraph></td><td><paragraph>1</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Intracranial hemorrhage</paragraph></td><td><paragraph>3</paragraph></td><td><paragraph>2</paragraph></td></tr></tbody></table>